Sickle cell disease is caused by the homozygous missense mutation of Glu to Val in codon 6 of the hemoglobin (Hb) β chain gene, encoding the mutant βS globin polypeptide. In the absence of wildtype β globin, assembly of tetrameric α2βS2 generates sickle hemoglobin (HbSS). Polymerization of deoxy-HbSS leads to oxidation, crosslinking, stiffening, and distortion of the red cell membrane, increased adhesiveness to leukocytes and to endothelial cells, and cell lysis. The resulting hemolytic anemia and diffuse vaso-occlusive pathology causes life-long illness for which the only currently approved chronic drug treatment is hydroxyurea, supplementing the traditional mainstays of symptomatic treatment: hydration, pain relief, anti-inflammatory drugs, and antibiotics. Marrow transplantation can be curative, but the associated morbidity remains high enough to discourage its widespread use even in developed countries. Although gene therapy continues to show promise, development of adjunct pharmacotherapy remains a high priority for treatment and management of sickle disease.
It has been reported that mature human sickle red cells (SS cells) are dehydrated by inappropriate hypoxic activation of erythroid K—Cl cotransporters and of the erythroid Ca2+ activated K+ channel KCa3.1/IK1/KCNN4, also known as the “Gardos channel” (Brugnara et al. 2001, Drug news & perspectives 14(4): 208-220; Steinberg and Brugnara 2003, Annual review of medicine 54: 89-112; Begenisich et al. 2004, The Journal of biological chemistry 279(46): 47681-47687; Rust et al. 2007, The Journal of clinical investigation 117(6): 1708-1717). The consequent elevation of intracellular [HbSS] dramatically shortens the “delay time” (Mozzarelli et al. 1987, Science (New York, N.Y. 237(4814): 500-506) for assembly of the critical aggregate of deoxy-HbSS tetramers required for subsequent rapid growth of deoxy-HbS fiber length (Christoph et al. 2005, Biophysical journal 88(2): 1371-1376). Current therapeutic approaches involve inhibition of erythroid K—Cl cotransporters with magnesium pidolate (Hankins et al. 2008, British journal of haematology 140(1): 80-85), the KCa3.1 inhibitor ICA-17043 (senicapoc) (Ataga et al. 2008, Blood 111(8): 3991-3997) and endothelin antagonists (Sabaa et al. 2008, The Journal of clinical investigation, Vol. 118(5):1924-33).